A number of immunotherapeutic approaches proposed for the treatment of tumors have had limited success. For example, the use of exogenous antibodies or immunotoxins specific for tumor associated antigens (TAAs) has been attempted for the targeted killing of tumor cells. However, successful treatment has been hampered, in part, by the relative inaccessibility of the tumor cells to the circulating, exogenously administered antibodies.
Other approaches have been designed to elicit a host immune response against the tumor cells. Indeed, there is strong evidence suggesting that the stimulation of a potent and specific T-cell response against tumor cells will result in tumor reduction. However, although most cancer cells express tumor associated antigens (TAAs), the presence of a tumor usually does not result in the induction of tumor-specific immunity. Attempts to increase the poor immunogenicity of tumor cells comprise most of the history of cancer immunotherapy. These efforts have included physical modification of the tumor cells (including γ-irradiation), the inoculation of mixtures of tumor cells and pathogens (viruses, bacteria and bacterial extracts) and more recently, gene-modification of the tumor cells with a variety of immunomodulatory molecules.
In the case of vaccination in the treatment and/or prevention of cancer, a potentially effective strategy for eliciting vigorous immune responses against TAAs may involve the insertion of the cloned genes encoding TAAs into recombinant viruses (reviewed in Restifo, 1996, Curr. Opin. Immunol. 8:658-663). A number of recombinant expression vectors have been shown to be useful in the prevention, and in some cases in the treatment, of tumors in experimental animals including poxviruses (vaccinia (Hodge, et al., 1995, Int. J. Cancer 63:231-237)), fowlpox (Wang, et al., 1995, J. Immunol. 154:4685-4692) and canary pox (Plotkin, et al., 1995, Dev. Biol. Stand. 84:165-170)); adenoviruses (Chen, et al., 1996, J. Immunol. 156:224-231; Randrianarison-Jewtoukoff and Perricaudet, 1995, Biologicals 23:145-157); polioviruses (Ansardi, et al., 1994, Cancer Res. 54:6359-6364); Sindbis viruses (Johanning, et al., 1995, Nucleic Acids Res. 23:1495-1501) and non-viral vectors including plasmid DNA administered by injection (Conry, et al., 1995, Gene Ther. 2:59-65) and by “gene gun” (Irvine, et al., 1996, J. Immunol. 156:238-245).
However, the foregoing systems have limitations which restrict their use in humans. For example, pre-existing immunity to vaccinia or adenovirus precludes their use as vaccinating strains. Moreover, the immune response induced by vaccinia or adenovirus precludes the use of the same virus for a second immunization or boost. In addition, the pathogenicity associated with some virus vectors, e.g., adenoviruses, also severely limit their use in vaccine formulations for human patients. Thus, there is a need for the continued exploration of new vector systems for use in cancer vaccines.